In 1998, in response to an NIH invitation (PA-96-050) for investigator-initiated research on genetic factors that may be important in the development of Parkinson Disease (PD) a collaborative research effort to identify susceptibility genes for PD was established between Indiana University and investigators currently at the University of Rochester, the Parkinson Study Group (PSG), the University of California, San Diego, Cincinnati Children's Hospital Medical Center, and the University of California, Irvine. During the first 4.5 years of this grant award, 422 multiplex PD families with 550 affected sibling pairs were recruited and rigorously evaluated. These genetically informative families were used to examine the role of the parkin gene in familial Parkinson's disease. Additionally, a genome screen was completed and evidence of linkage to chromosomes 2, 10 and X was consistently found in these family-based samples. During the next 5 years, we propose to extend our current results to: 1) continue to ascertain multiplex families with PD and thereby increase our power to detect and isolate PD susceptibility genes;2) further examine the role of the parkin gene in PD through careful clinical evaluation of families with known parkin mutations;3) identify the genes contributing to PD susceptibility in our multiplex families;and 4) test the role of any putative candidate genes identified through our family-based studies in a sample of sporadic PD cases and unaffected controls. In this way, we will expand the understanding of the etiology, pathogenesis, diagnosis, and ultimately, the prevention of this disease. To accomplish these goals we will focus on the following Specific Aims: 1. Expand the family resources so as to increase the power to identify the genes contributing to PD susceptibility. 2. Study the role of parkin mutations in Parkinson's disease. 3. Perform molecular studies to identify PD susceptibility genes. 4. Evaluate putative PD susceptibility genes in a case-control sample.